ABSTRACT ? This Alzheimer?s Disease (AD) Supplement application (NOT-AG-18-039) represents an extension of our currently funded R01AG054538 Ace2 As A Novel Therapeutic To Preserve Physical Function In Late Life in which we study the impact of modulating the renin-angiotensin system (RAS) on age-related declines in physical function. Here we propose to apply the same interventions used in the parent grant to the study of cognitive frailty and AD. Cognitive frailty (simultaneous physical frailty and cognitive impairment) represents an enormous clinical and public health challenge given the rapid aging of the worldwide population. Individuals presenting with cognitive frailty have an increased risk for AD and other dementias. AD itself is a progressive neurodegenerative disorder, with no effective method for treatment despite extensive research focused on the brain as the target organ. We propose an exciting paradigm shift: directing intervention to the gut microbiome as the target ?organ? to treat cognitive frailty symptoms and mitigate the progression of AD. We have developed an innovative intervention whereby an orally-delivered probiotic incorporates delivery of angiotensin (1-7) [Ang(1-7)] to the gut. Ang(1-7) is a key vasoprotective effector of the RAS and the enzyme responsible for its production, angiotensin converting enzyme 2 (ACE2), is abundant in the healthy gut. Importantly, recent data from human and rodent studies suggest that severity of AD is inversely correlated with circulating levels of Ang(1-7) and ACE-2. Here, we propose to address the hypothesis that the Ang(1-7)- expressing probiotic will improve cognition in aged F344/BN rats and two preclinical models of AD: the Tg344- AD rat and the hAPP,hBACE AD flies. Understanding the relationship between RAS, gut integrity, and cognitive function is a new frontier in aging and AD risk research. Preclinical rodent models are invaluable; however, Drosophila represents an ideal model as well: high throughput screening capabilities, low cost, fast reproduction and an easily manipulated microbiome. Enzymes regulating RAS, are present in Drosophila, and the fly ACE gene, AnCE, is inhibited by the same drugs that inhibit ACE in humans. A recent paper suggest that enteric infection exacerbates inflammation and neurodegeneration in a fly model of AD. However, the use of probiotics, whether genetically modified or otherwise, has yet to be studied using fly models of AD. Global Specific Aim: Orally-administered probiotic expressing Ang (1-7) will enhance gut integrity, reverse gut dysbiosis, reduce intestinal, systemic and tissue-specific inflammation, and improve cognitive function using validated, comparative models of aging and AD: a) F344/BN rat; b) Tg344AD rat; c) hAPP, hBACE AD fly.